Project Summary/Abstract Stress is a leading risk factor for a multitude of the most prevalent mental health illnesses worldwide, including major depressive disorder (MDD). Current treatments fall short of what is required to meet the ever increasing disease burden and opportunity cost. In addition, current treatment paradigms fail to alleviate underlying pathophysiologies and a significant percentage of patients become refractory to treatment. The purpose of Research Project 2 is to investigate whether a well-characterized polyphenol enrich botanical supplement can provide an alternative approach to suppress the pathological effects of stress that increase an individual's susceptibility to developing certain psychiatric disorders. Emerging evidence has demonstrated that susceptibility to stress is a function of both central and peripheral immune activity. In particular, select inflammatory mediators, such as interleukin (IL)-6, have recently been recognized as key mechanistic contributory factors of stress-induced anxiety and depression. Supporting this principle are clinical observations that show that a subset of patients with treatment-resistant depression exhibit increased expression of IL-6 in the plasma. We show in a model system of stress-induced depression that specific bioavailable metabolites of our botanical supplement suppress stress-induced production of IL-6 from leukocytes and, further, provide resilience to stress-induced psychological impairment. Therefore, the first objective of Research Project 2 will be to thoroughly the pharmacokinetic and steady state properties of our botanical supplement to confirm that the bioactive compounds that were found to modulate IL-6 expression in rodents are also bioavailable and reach a bioactive concentration in humans. We will conduct a double blind, randomized, placebo-controlled (untreated control), dose ranging study in healthy volunteers using a low dose, intermediate dose, and high dose of BDPP, based upon our work with animals and from the scientific literature. Project 2 then investigate the association between metabolites of our botanical supplement and the expression of inflammatory cytokines in healthy subjects. Our proposed experiments will then characterize whether BDPP metabolites prevent upregulation of IL-6 in response to the Trier Social Stress Test: a well-validated model of psychological stress. Moreover, by integrating a multivariate adaptive regression splines (MARS) statistical method we can determine which metabolite, or combination of metabolites, may be responsible for suppressing IL-6 in a clinical setting in response to stress. Objectives from Research Project 2 will inform a future clinical trial by providing guidance on the optimal product dose, treatment timing, outcome markers of bioavailability; will verify metabolites that suppress IL-6 expression are present at bioactive concentrations in plasma, and establish whether anti-inflammatory properties of BDPP observed in model systems of stress- induced depression can be recapitulated in a clinical model of stress.